Numerous antifungal agents have been developed, and newer agents are on the horizon. The increasing number of immunosuppressed patients and the expansion of drug resistance of microorganisms make the development and appropriate use of antimicrobial agents two of the most important areas in microbiology and infectious diseases. This section is meant only to introduce the reader to the more commonly used antifungal agents; it is by no means comprehensive. Also, this section is not to be used as a guide for therapy. Therapeutic guidelines may be found in the texts listed in the bibliography.
POLYENE MACROLIDE ANTIFUNGALS
Polyene macrolide antifungal agents consist of a group of complex organic molecules, most of which contain multiple, conjugated, double-bond and one- to three ring structures. This group includes many of the most commonly used antifungal agents, such as amphotericin B, the colloidal and liposomal preparations of amphotericin B, nystatin, and griseofulvin.
Amphotericin B
Amphotericin B is produced by the actinomycete Streptomyces nodosus. It is commonly infused intravenously to treat deep-seated fungal infections (e.g., invasive aspergillosis), and those caused by Candida spp., Cryptococcus spp., and members of the Mucorales. Amphotericin B binds the ergosterol component of the fungal cell mem brane and alters the selective permeability of this mem brane. However, other sterols, including those present in mammalian cell membranes, are also bound. The most significant adverse reaction associated with amphotericin B therapy is renal insufficiency. The liposomal amphotericin B compounds reportedly diminish this adverse reaction. Although amphotericin B is active against a wide variety of fungi, resistant organisms exist, which the laboratory must be able to identify. Fungi resistant to amphotericin B include Pseudallescheria boydii, Aspergillus terreus, Trichosporon spp., and in most cases Fusarium spp.
Nystatin
Nystatin, an antifungal antibiotic produced by Streptomyces noursei, is not absorbed in the gastrointestinal tract. It is principally used locally to treat oral or vulvovaginal candidiasis. The toxicity of this drug is prohibitive to parenteral use.
Griseofulvin
Griseofulvin is an antifungal antibiotic produced by a species of Penicillium. Its mechanism of action consists of binding microtubular proteins, which are required for mitosis. Griseofulvin is an oral agent used to treat dermatophytoses, which are not responsive to azole antifungal therapy. Headache, gastrointestinal disturbances, and photosensitivity are a few of the adverse reactions that limit the usefulness of this drug.
5-Fluorocytosine (Flucytosine)
Flucytosine is a pyrimidine base, which is fluorinated in the fifth position. Flucytosine is metabolized to 5-fluorouracil, which is incorporated into fungal RNA. This subsequently inhibits protein synthesis. Flucytosine is also metabolized into fluorodeoxyuridine mono phosphate, a potent inhibitor of DNA synthesis. Flucytosine and amphotericin B act synergistically and have been used in combination therapy for treating infections by Candida spp. and Cryptococcus spp. Side effects and the emergence of resistance have limited its usefulness.
AZOLE ANTIFUNGAL DRUGS
The azole group of antifungal agents consists of the imidazoles and the triazoles. These compounds contain six carbon ring structures with conjugated double bonds, chloride residues, and five carbon ring structures that contain at least two nitrogen molecules. Traditionally used agents in this group include clotrimazole, miconazole, fluconazole, itraconazole, voriconazole and ketoconazole. The newer triazoles are voriconazole, posaconazole and, most recently, ravuconazole; of these only voriconazole is discussed here, because it was the first of the newer agents released and has been the most thoroughly reviewed. Azole antifungal agents disrupt the integrity of the fungal cell membrane by interfering with the synthesis of ergosterol.
Clotrimazole and Miconazole
The synthetic imidazoles clotrimazole and miconazole are covered together because of their many similarities. These agents are available for topical or intravaginal application. They are useful in mild cases of dermatophytosis, including tinea versicolor. Adverse reactions are generally limited to burning, itching, and/or skin irritation.
Fluconazole
Fluconazole, a triazole, is exceptionally soluble in water, which allows either oral or intravenous administration. Fluconazole has excellent activity against most Candida spp. and Cryptococcus spp. therapeutic levels are easily reached in the central nervous system. Side effects of fluconazole therapy are usually minimal. The susceptibility of C. glabrata to fluconazole is not predictable. Isolates of C. glabrata may be susceptible, dose-dependent susceptible, or resistant to fluconazole. Other notable yeasts or yeastlike fungi resistant to fluconazole are Candida krusei and Rhodotorula spp.
Ketoconazole
Ketoconazole is an imidazole that is either taken orally or applied topically. It is useful in mild cases of paracoccidioidomycosis and is an alternative to amphotericin B for infections caused by Blastomyces or Histoplasma spp. Ketoconazole may be used if prolonged oral therapy for chronic mucocutaneous candidiasis is needed. One group has reported some success in the treatment of P. boydii infections with ketoconazole. In vivo, ketoconazole is fungistatic, because fungicidal levels are not achievable with therapeutic concentrations. Adverse reactions include transient elevations in liver enzymes, nausea, and dose-related gynecomastia, decreased libido, and oligospermia in males.
Itraconazole
The triazole itraconazole has a spectrum of activity that encompasses that of ketoconazole. In addition, itraconazole has been shown to be effective in cases of aspergillosis, sporotrichosis, cryptococcosis, and onychomycosis. Adverse reactions principally include gastrointestinal disturbances; however, vestibular disturbances, edema, and skin irritations have been reported.
Voriconazole
Voriconizole, one of the new triazoles, has an expanded spectrum of activity compared with itraconazole. In addition to the uses described previously for itraconazole, voriconazole demonstrates useful activity against some Fusarium strains and against fluconazole-resistant yeasts, such as C. krusei and C. glabrata. However, it is important to note that the Mucorales are resistant to voriconizole. Elevated liver enzymes may occur, as may transient visual disturbances, which can significantly alarm the patient if the individual is not forewarned.
Posaconazole
Posaconazole is a triazole structurally similar to voriconazole. Posaconazole is an oral azole that is effective against dermatophytes, including Candida spp., Aspergillus terreus, Fusarium spp., and Mucorales.
Anidulafungin
Anidulafungin is a broad-spectrum echinocandin. It is a selective inhibitor of the fungal enzyme beta-(1,3)-D glucan synthase that is involved in fungal cell wall synthesis. The drug is effective against Candida spp., including strains that are resistant to fluconazole.
Micafungin
Micafungin is an echonocandin. The drug is a selective inhibitor of the fungal enzyme beta-(1,3)-D-glucan synthase that is involved in fungal cell wall synthesis. It is used for the propylaxis and treatment of Candida spp. infections in adult and pediatric patients.
OTHER
Terbinafine (Lamisil) Terbinafine is a synthetic allylamine that is highy liphophilic, allowing it to accumulate in the skin, nails, and fatty tissue. The drug interferes with fungal cell wall synthesis and is an effective topical treatment for infections.
ECHINOCANDINS
The echinocandins are glucan synthesis inhibitors. More specifically, they inhibit 1, 3 beta-glucan synthase, an enzyme important in fungal cell wall synthesis. These drugs lead to cellular osmotic instability. The three echinocandins are caspofungin, micafungin, and anidulafun gin. Caspofungin was the first to be released and is the representative compound for this group.
Caspofungin
Caspofungin is fungicidal against Candida spp., including species that are or may be resistant to fluconazole (e.g. C. krusei and C. glabrata, respectively). It is fungistatic rather than fungicidal against Aspergillus spp. It is important to note that C. neoformans var. neoformans is intrinsically resistant to caspofungin. Caspofungin also is not likely to be useful against Trichosporon spp., Rhodotorula spp., or the Mucorales. Side effects are minimal.
Selenium Sulfide
Selenium sulfide shampoos, available commercially, dis close antifungal activity against Malassezia furfur, the causative agent of tinea versicolor. Additionally, selenium sulfide is sporicidal for Trichophyton tonsurans and therefore may be used as an adjuvant to griseofulvin therapy.
Potassium Iodide
Potassium iodide is the therapy of choice for cutaneous/ lymphatic sporotrichosis. Localized heat therapy may be used adjunctively. Some individuals are allergic to potassium iodide. Adverse reactions include a bitter taste, allergic rash, and anorexia.
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